ABSTRACT The delta cell of the pancreatic islet has been barely investigated despite secreting somatostatin (SST), a powerful inhibitory peptide that is essential for the homeostasis of different tissues. In the islet, SST inhibits the secretion of insulin and glucagon, but little is known about the mechanisms that activate delta cell and SST secretion. No other roles have been investigated or even proposed for the delta cell in islet biology and glucose metabolism. The nervous system, endocrine organs, and local neighboring cells, including immune cells, could potentially interact with the delta cell as a ?switch? or ?brake? to modulate the function of the whole islet. It is clear that the relevance of this powerful inhibitory component in the islet has been overlooked. The position of the delta cell as a key element in the regulation of islet hormone secretion needs to be addressed to understand how islet hormone secretion is regulated. The general hypothesis of this proposal is that the delta cell is a signaling hub where paracrine, immune and nervous signals converge and are integrated to set the level of SST secretion that ultimately modulates overall islet activity. This hypothesis will be tested through two related but not interdependent aims. In Aim 1 we will study the role of GABA as a key paracrine signal in delta cell function. Our previous results suggest that delta cell function is tightly adjusted by GABA, a paracrine signal secreted by beta cells through glucose independent mechanisms. GABA could therefore modulate delta cell responses to other local signals. We will use human islets and, when translatable, mouse islets to determine (1.1) the effects of endogenous GABA on the magnitude of basal SST secretion, (1.2) the effects of endogenous GABA on delta cell responses to glucose and other, local signals, and (1.3) how loss of endogenous GABA signaling contributes to the changes in somatostatin secretion in high BMI and type 2 diabetes. In Aim 2 we will examine the role of the delta cell and SST signaling in islet inflammation. Our preliminary findings indicate that the delta cell responds to signals from the immune and neural compartments and secretes SST to counteract inflammation and neuroinflammation. Thus, the delta cell could protect the islet from unchecked and damaging immune responses. We will test (2.1) the effects of cytokines and proinflammatory neuropeptides on delta cells, and (2.2) the effect of SST on local immune cells and sensory nerves. We will use a combination of novel in vitro (isolated islets), ex vivo (pancreatic tissue slices), and in vivo (intraocular islet grafts) approaches together with pharmacological tools, optogenetic stimulation, cell ablation, functional imaging and systemic metabolic readouts to study how delta cells are activated and how they influence the sensory nerves and surrounding endocrine and immune cells. We expect our studies to further our understanding of the circumstances under which the delta cell is recruited to influence endocrine and immune cells in the islet. If SST?s role as an immunomodulator is validated, it is likely that the delta cell will be reconsidered as a key element in the natural history of diabetes. Therefore, important advances in our understanding of the pathogenesis of diabetes could be expected.